Multiple system atrophy (MSA) is a sporadic multi-system progressive and uniformly fatal disorder characterized by autonomic failure, with orthostatic hypotension, neurogenic bladder/erectile dysfunction, cerebellar ataxia, corticospinal dysfunction, plus parkinsonism or cerebellar degeneration. Neuropathologically, MSA is characterized by glial cytoplasmic inclusions (GCI) of abnormally aggregated o synuclein (a-syn). Current treatments approaches aimed at symptomatic relief do not stay progression of disease and death, so that strategy has shifted to approaches aimed at halting or reversing pathogenesis of MSA. Many lines of evidence highlight the pathological importance of a-syn aggregation. There is evidence to support roles for mitochondria! dysfunction and oxidative stress. A transgenic (tg) mouse model expressing human a-syn under the myelin basic protein (MBP) promoter is now available. These MBP-a-syn tg mice have been shown to exhibit the oligodendroglial aggregates of a-syn and motor deficits characteristic of MSA. A number of agents have shown promise in combating a-syn aggregation. Of particular interest is rifampicin, because of its ability to inhibit the formation of a-synuclein fibrils and disaggregate fibrils already formed. This has led to the hypothesis that the antibiotic will delay progression or reverse neurologic and autonomic functions and symptoms in MSA. This approach has been supported by recent studies demonstrating a reversal of pathology and function. We propose a double blind placebo controlled clinical trial of Rifampicin 600 mg per day for 12 months in 60 tolOO patients with MSA. The study cohort will comprise patients with relatively early MSA, defined by duration of disease (<4 years) and severity, to optimize chances of improvement. The primary endpoint will be part 1 of the Unified MSA Rating Scale (UMSARS1). Secondary endpoints will comprise changes in autonomic symptom scores (COMPASS_change_select), and other autonomic indices. This consortium brings together a unique collaboration of autonomic experts with expertise to undertake a key study on the pathogenesis of MSA. Such a study may only be possible because this consortium enables a collaborative synergistic relationship with the 4 institutions (Vanderbilt, Mayo, Harvard, New York) and its collaboration with the MSA PPG.